Neurotrophic factors are a family of proteins that are responsible for the growth and survival of nerve cells during development, and for the maintenance of adult nerve cells. Animal studies and test tube (in vitro) models have shown that certain neurotrophic factors are capable of making damaged nerve cells regenerate. Because of this capability, these factors represent exciting possibilities for reversing a number of devastating brain disorders, including Alzheimer’s disease, Parkinson’s disease, Lou Gehrig’s disease, and Huntington’s Disease (HD). (For more information on how HD relates to Alzheimer’s and Parkinson’s, click here.) Currently, scientists are looking for ways to harness neurotrophic factors and somehow induce the damaged nerve cells to regenerate in order to improve the symptoms of people with neurological disorders.
One neurotrophic factor that is particularly relevant to HD is Brain-derived neurotrophic factor (BDNF). BDNF levels are decreased in the brains of HD patients, which might be partly responsible for the degenerative processes of HD. Researchers have recently discovered a link between BDNF, mutant huntingtin, and excitotoxicity, a process by which brain cells die after stimulation. The mutant huntingtin protein invariably leads to the death of nerve cells in the striatum, the region of the brain needed for movements; however, how mutant huntingtin does this damage is unclear. One possibility is that mutant huntingtin lowers levels of BDNF, making nerve cells more susceptible to injury and death. Therefore, therapeutic approaches aimed at increasing BDNF production may be able to counteract the effects of mutant huntingtin and prevent a significant amount of the neurodegeneration that would otherwise occur in HD. (For more information on huntingtin protein, click here.)
What role does BDNF play in HD pathology?^
BDNF has been shown to play a role in neuroplasticity, which allows nerve cells in the brain to compensate for injury and new situations or changes in the environment. (For more information on neuroplasticity, click here.) The central nervous system (CNS) has a greater ability to recover from insult or injury than scientists had previously thought. For decades, the prevailing view was that the brain stopped developing after the first few years of life. Connections between the brain’s nerve cells could only be formed during a critical period early in life. After this critical period, it was thought that the brain was unable to form new connections. Thus, if a particular area of the adult brain was damaged or injured, nerve cells would not be able to regenerate, and the functions controlled by that area would be lost forever. However, new research suggests that this view is not entirely correct. Researchers now recognize that the brain continues to reorganize itself by forming new neural connections throughout life. Neurotrophic factors, such as BDNF, promote the survival and aid in the regeneration of adult neurons.
As mentioned above, the mutant huntingtin protein is harmful to striatal nerve cells in the brain. It also decreases transcription of BDNF, which results in a decrease BDNF production in people who have HD. Nerve cells require BDNF to survive, but also to regenerate. Less BDNF means less neuroplasticity so the striatal nerve cells are less capable of compensating for injuries. By lowering levels of BDNF in the brain, mutant huntingtin acts as a devastating double-edged sword. First, nerve cells die because there isn’t enough BDNF to effectively combat neurodegeneration. Second, nerve cells are not able to regenerate because there still isn’t enough BDNF. It therefore appears that BDNF plays a crucial role in the degenerative process of HD.
How does BDNF work?^
In the brain, BDNF is released by either a nerve cell or a support cell, such as an astrocyte, and then binds to a receptor on a nearby nerve cell. (For more information on HD neurobiology, click here.) This binding results in the production of a signal which can be transported to the nucleus of the receiving nerve cell. There, it prompts the increased production of proteins associated with nerve cell survival and function.
Can exercising promote BDNF production?^
Scientists are increasingly recognizing the capacity of physical activity to maintain and compensate for deterioration of nerve cell function. Numerous animal studies have reported that voluntary exercise leads to increased BDNF production. In rats, several days of voluntary wheel-running increased levels of BDNF in the hippocampus. This finding is surprising considering that the hippocampus is a structure normally associated with higher cognitive functions such as emotion and memory rather than motor activity. The changes in BDNF levels were found in nerve cells within days in both male and female rats and were sustained even several weeks after exercise.
Similarly, scientists studying HD in mouse models found that HD mice given the opportunity to exercise expressed more BDNF in the striatum than HD mice that didn’t exercise. This is notable because people with HD have particularly low levels of BDNF in the striatum, which is thought to be part of the reason that the striatum is the main site of neurodegeneration in people with HD. Furthermore, motor and cognitive symptoms set in later for HD mice that ran,
In order for exercise to be used as a therapeutic strategy the type and duration of exercise would need to be determined and probably individualized to each patient. There is debate over what intensity of exercise is best to promote brain health. Although previous reports showed that only rigorous exercise, like treadmill running, stimulated BDNF expression, researchers have more recently found that even a light exercise routine may be sufficient. The downside of high intensity is that sometimes this kind of exercise can be a stressful experience that increases the release of stress hormones, thereby canceling the BDNF-promoting effects of exercise. Also, many individuals are simply unable to perform rigorous exercise. These new reports are very encouraging because they indicate that everyone can enjoy the benefits of exercise by simply engaging in light activities such as walking or doing yard work. (For more information on exercise and HD, click here).
Can BDNF be used to treat HD?^
The discovery of the relation between huntingtin and BDNF is a major step in the path to finding a treatment for HD. Previously, it was thought that mutant huntingtin gained a new function that caused neurodegeneration in the brain. However, researchers now know that HD is caused, not only by this toxic gain of function of mutant huntingtin, but also by a loss of function of normal huntingtin. Normal huntingtin allows BDNF production and plays a role in moving BDNF to the places it is needed most. In the absence of normal huntingtin, BDNF production drops drastically. This realization is a major step toward HD treatment because it indicates that therapeutics need to be aimed not only at preventing mutant huntingtin toxicity, but also at restoring normal huntingtin function.
A simple way to restore the loss of normal huntingtin function in the case of decreased BDNF production would be to administer BDNF itself. However, when BDNF is taken by routes common for other drugs, such as orally or injections into the body, it can’t reach the brain where it is needed; there is a barrier – the blood-brain barrier – that makes it difficult for substances to pass between the body and the brain. So numerous laboratories are currently trying to develop ways to deliver BDNF to the brain. However, there are still several steps that need to be taken before a drug can be developed based on this research. Scientists need to understand exactly how huntingtin “communicates” to the BDNF gene to increase its activity. Trials are already under development to deliver BDNF via gene therapy to HD transgenic mice and researchers are confident that research in this area will progress rapidly.
Research on BDNF Inducers^
Citalopram is an anti-depressant that is currently on the market to treat people with depression, and goes by the brand-name Celexa. Citalopram is a particular type of anti-depressant called a selective serotonin reuptake inhibitor (SSRI). This class of anti-depressants are believed to raise BDNF levels; SSRIs cause an increase in serotonin levels, which causes nerve cells to make more BDNF. Therefore, SSRIs are being investigated for their potential ability to slow the progression of HD – as described in more detail here.
Scientists are now investigating how citalopram might help people with HD in a phase II clinical trial called CIT-HD. Scientists will study the effect of citalopram on attention, thinking, muscle movements, and daily activities. The study will last for 20 weeks, and is currently enrolling participants. For more information about CIT-HD, or to participate in the trial, please click here.
Ampakines are a type of drug that have recently caught the eye of the scientific community for their potential to raise BDNF levels. Cortex Pharmaceuticals Inc. is actively developing and researching the use of ampakines for treatment of various neurological disorders, including HD.
(Simmons et al. 2010): Scientists treating HD mice with ampakines are finding promising results. HD mice injected with ampakines twice a day have normal levels of BDNF. Additionally, several other symptoms of HD, such as striatal atrophy and aggregation of the mutatnt huntingtin protein, were decreased by ampakine treatment. These scientists also tested the behavior of the mice to see whether ampakine treatment was helpful in fighting the effects of the HD mutation. The motor symptoms that HD mice display were significantly improved in HD mice that were given ampakine treatment before their symptoms had begun. Another symptom that HD mice and patients display – problems with memory – seemed to be aided by ampakine treatment. Further studies are needed to verify these findings, but this study and others suggest that ampakines are a promising avenue of research.
Cystamine is a drug that might combat HD in several ways. Apart from the fact that it is thought to raise levels of BDNF, cystamine might also inhibit protein aggregation (the process by which ‘clumps’ of mutant huntingtin form), and has antioxidant properties. Raptor Pharmaceuticals is currently studying cystamine in phase II clinical trials. For more information on cystamine and the on-going clinical trial, please read the HOPES article here.
For further reading^
1. Connor, J. et al. (1997). Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: evidence for anterograde axonal transport. Society for Neuroscience 17(7): 2295-2313.
This article is fairly complex. It describes the likely method through which BDNF exerts its effects within the brain.
2. Gomez-Pinilla, F., Ying, Z., Roy, R., Molteni, R., & V. Edgerton. (2002). Voluntary exercise induces a BDNF-mediated mechanism that promotes neuroplasticity. J Neurophysiol. 88(5): 2187-95.
This article is easy to understand and it describes the effect of exercise on brain health and plasticity.
3. Vaynman, S., Ying, Z., & F. Gomez-Pinilla. (2003). Interplay between brain-derived neurotrophic factor and signal transduction modulators in the regulation of the effects of exercise on synaptic-plasticity. Neuroscience 122(3): 647-57.
This article is fairly easy to read and it discusses the possible mechanisms through which exercise may influence levels of BDNF.
4. Simmons DA, Mehta RA, Lauterborn JC, Gall CM, Lynch G. Brief ampakine treatments slow the progression of Huntington’s disease phenotypes in R6/2 mice. Neurobiol Dis. 2011 Feb;41(2):436-44.
A technical article that describes how ampakines raise BDNF levels in HD mice
5. Zuccato C. et al. (2001) Loss of huntingtin-mediated BDNF gene transcription in Huntington’s disease. Science, 293, 493-496.
This is a technical article that describes how the beneficial activity of huntingtin is lost in people with HD and how this leads to decreased production of BDNF.
6. Zuccato C., Tartari T., Crotti C., Goffredo D., Valenza M., Conti L., Cataudella T., Leavitt B. R., Hayden M. R.,Timmusk T., Rigamonti D. & Cattaneo E. (2003) Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nature Genetics 35: 76-83.
This article is very technical. It describes in detail how normal huntingtin increases transcription of BDNF by silencing NSRE.
D. McGee, 1-1-06, Updated by M. Hedlin 9.27.11